Project Summary/Abstract Retinal pigment epithelial (RPE) cells of the eye amass a complex mixture of vitamin A aldehyde adducts with age. These fluorophores have bisretinoid structures, form randomly in photoreceptor cells due to inadvertent reactions and accumulate as the lipofuscin of the cells. The damaging effects of these compounds on RPE cells are implicated in a number of age-associated and early-onset forms of retinal disease including recessive Stargardt disease and age-related macular degeneration. The adverse effects of these pigments are likely due, at least in part, to their propensity to photogenerate reactive oxygen species and to photodegrade into dicarbonyl and aldehyde-bearing fragments. The broad objectives of the studies proposed in this application are to understand mechanisms by which bisretinoids of retina contribute to disease processes that threaten vision. We aim to elucidate therapeutic possibilities and to contribute to interpretations of fundus autofluorescence. We will address both the bisretinoid pigments constituting RPE lipofuscin and the bisretinoid precursors of these compounds in photoreceptor cells. This work will elucidate therapeutic avenues. Additionally since bisretinoids are the major source of fundus autofluorescence, these studies will contribute to clinical interpretations of fundus autofluorescence images. In Specific Aim 1, we will explore interactions between CS and RPE bisretinoids. We will determine whether constituents of CS accelerate bisretinoid lipofuscin formation and outer nuclear layer thinning in Abca4-/- mice. We will investigate interactions between the oxidative stress imposed by cigarette smoke exposure and the photoxidative insult resulting from the deposition of bisretinoids in RPE. In Specific Aim 2, we will explore amine-carrying small molecules for their ability to reduce bisretinoid formation and/or to scavenge carbonyls released by photodegradation of bisretinoid. In Specific Aim 3 we will probe the sources of short-wavelength and near-infrared fundus autofluorescence. These aims will be achieved using animal and in vitro models and by employing biochemical, histological and cellular assays. Completion of this research will advance our understanding of risks associated with age-related macular degeneration and will contribute to an understanding of how light and oxidative mechanisms are factors in photoreceptor cell death in age-related and monogenic retinal disorders.